ObjectivesTo determine the repeatability and response to therapy of dynamic contrast-enhanced (DCE) MRI biomarkers of synovitis in the hand and wrist of rheumatoid arthritis (RA) patients, and in particular the performance of the transfer constant K trans, in a multicentre trial setting.MethodsDCE-MRI and RA MRI scoring (RAMRIS) were performed with meticulous standardisation at baseline and 6 and 24 weeks in a substudy of fostamatinib monotherapy in reducing synovitis compared with placebo or adalimumab. Analysis employed statistical shape modelling to avoid biased regions-of-interest, kinetic modelling and heuristic analyses. Repeatability was also evaluated.ResultsAt early study termination, DCE-MRI data had been acquired from 58 patients in 19 imaging centres. K trans intra-subject coefficient of variation (N = 14) was 30%. K trans change demonstrated inferiority of fostamatinib (N = 11) relative to adalimumab (N = 10) after 6 weeks (treatment ratio = 1.92, p = 0.003), and failed to distinguish fostamatinib from placebo (N = 10, p = 0.79). RAMRIS showed superiority of fostamatinib relative to placebo at 6 weeks (p = 0.023), and did not distinguish fostamatinib from adalimumab at either 6 (p = 0.175) or 24 (p = 0.230) weeks.ConclusionThis demonstrated repeatability of K trans and its ability to distinguish treatment groups show that DCE-MRI biomarkers are suitable for use in multicentre RA trials.Key Points • DCE-MRI biomarkers are feasible in large multicentre studies of joint inflammation. • DCE-MRI K trans showed fostamatinib inferior to adalimumab after 6 weeks. • K trans repeatability coefficient of variation was 30% multicentre. Electronic supplementary materialThe online version of this article (doi:10.1007/s00330-017-4736-9) contains supplementary material, which is available to authorized users.
Background Secukinumab (fully human IgG1k anti-IL17A monoclonal antibody) significantly improved clinical signs and symptoms of active ankylosing spondylitis (AS) patients enrolled in a recent proof-of-concept (PoC) study. Magnetic resonance images (MRI) of these patients (pts) showed reduction of spinal inflammation at week (W) 6 and W28 after initiation of treatment. Objectives To evaluate a subgroup of pts (N=13) in the open label extension study, who had MRI assessments at baseline (BL), W28 and W94. Methods In the 28W PoC study, 27/30 pts had sequential MRI studies, 22 had received secukinumab 2x10 mg/kg administered intravenously 3 Ws apart, and 5 pts had been randomised to placebo. 20 patients entered the extension study, 13 having MRI data at W94. Of these 13, ten were treated with secukinumab and 3 with placebo in the core study. In the extension study, all received secukinumab 14x3 mg/kg administered 4 Ws apart. MRIs (T1 and STIR) were rescored for this study. ASspiMRI-a scores and the occurrence of vertebral edges (VE) inflammatory and fatty lesions were evaluated by an independent blinded reader. Results All 13 pts completed this exploratory MRI substudy. In pts receiving 2x10 mg/kg secukinumab followed by 14x3 mg/kg (n=10) secukinumab, spinal inflammation was reduced compared to BL at W28 –similar to the results of the core study– and this reduction was sustained up to W94 (Fig 1). Also in 3 pts who had initially received placebo switching to secukinumab at W28, MRI inflammation at W94 was reduced. Of the 920 VEs evaluated, the proportion of VEs with inflammatory lesions was reduced from 9.9% (n=91) at BL to 3.7% (n=34) at W28 and 3.6% (n=33) at W94. In contrast, the proportion of fatty lesions at BL (13.5%, n=124) remained largely unchanged at W28 (14.3%, n=132) and W94 (13.7%, n=126). Image/graph Conclusions MRI analysis suggests that the IL-17 inhibitor secukinumab may reduce spinal inflammation and this effect may be sustained for up to 2 years, using a lower maintenance dose compared to the induction regimen. Notably, secukinumab appeared not to have any influence on fatty lesions. This observation contrasts recent reports of AS pts treated with TNF-blockers. The potential impact of these preliminary findings on radiographic progression under secukinumab therapy will be studied in larger trials. Disclosure of Interest X. Baraliakos: None Declared, J. Braun Grant/research support from: Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, EBEWE Pharma, Medac, MSD (Schering-Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi-Aventis, UCB, Consultant for: Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, EBEWE Pharma, Medac, MSD (Schering-Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi-Aventis, UCB, Speakers bureau: Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, EBEWE Pharma, Medac, MSD (Schering-Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi-Aventis and UCB, D. Laur...
BackgroundThe single-arm non-interventional study ICHIBAN was set up to evaluate the effectiveness and safety of intravenously administered Tocilizumab (TCZ IV) in patients (pts) with moderate to severe rheumatoid arthritis (RA) in Germany. Clinical data were collected during routine medical consultations including concomitant therapies, co-morbidities, therapeutic responses and adverse events.ObjectivesThis interim analysis assessed the effectiveness and safety of long-term TCZ IV treatment with respect to patients' age.MethodsSince February 2010 ∼250 German rheumatology study centres collected these prospective data. Pts were observed for a maximum period of 2 years (104 weeks). The present interim analysis included pts with complete baseline (BL) data before 03rd December 2015 (group total; n=2999). 902 pts have completed the maximal 104 week observation period (group W104). Subgroups according to age have been defined as <50 years, 50–65 years, >65 years.ResultsAt BL the age distribution showed the following proportions: <50 years 28.9%, 50–65 years 48.6%, and >65 years 22.5%. The mean TCZ IV treatment duration was 1.7, 1.8, and 1.7 years, respectively, for the three age groups.In comparison to younger pts, the elderly (>65 years) showed longer disease duration, higher inflammatory parameters, higher disease activity, and higher co-morbidity rates at BL. Nevertheless, TCZ IV showed comparable effectiveness in all age groups. At last visit, DAS28-BSG remission (<2.6) was reached by 55.2%, 51.6%, and 48.8% of pts aged <50, 50–65, and >65 years, respectively. The mean reduction from BL in DAS28-BSG was 2.6, 2.7, and 2.8, respectively.Regarding co-medication, the mean glucocorticosteroid (GC) dose was reduced from 7.1 (BL) to 4.6 mg/d (last visit) and was similar in all subgroups. About 12% of pts stopped GC therapy completely, again similar in all subgroups. At baseline, the rate of TCZ monotherapy (without concomitant sDMARD) was highest in the elderly (53.2%) while combination therapy is more common in younger pts (47.1%). The rate of sDMARD discontinuation while receiving TCZ is comparable in all subgroups (11.5%, 12.1%, 12.3%).Despite slightly higher incidence rates of adverse events (AE) and serious adverse events (SAE) for the elderly, the rates of infections, serious infections and TCZ discontinuation rates due to an AE did not increase with age (Table 1). Gastrointestinal perforation was rarely observed.ConclusionsTCZ IV treatment resulted in improvement of disease activity and reduction in concomitant GC dosing were observed. Despite higher disease burden at baseline, elderly RA patients (>65 years) benefited to the same extent as younger patients, without increased risk of infections. Considering natural age related risks, the low infection and gastrointestinal perforation rates of elderly patients seem to be attributable to the steroid sparing effect of TCZ therapy. Safety concerns should be no reason to argue against anti-IL-6 therapy in elderly patients.Disclosure of InterestC. Specker Consultant for...
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